Micro-RNAs (miRNAs) are small, stable RNA molecules that post-transcriptionally regulate gene expression in plants and animals. They act by base pairing to partially complementary sequences on target messenger RNAs to inhibit protein synthesis, primarily through translational repression and mRNA destabilization. More than 250 miRNAs are reportedly expressed in the retina, and miRNA gene regulation has been shown to impact retinal development, function, and disease. miRs -96, -183, and -182 comprise an evolutionarily conserved, paralogous gene cluster. Simultaneous partial disruption of the activities of these miRNAs in photoreceptors results in a robust light-induced retinal degeneration phenotype, implying that these miRNAs serve a neuroprotective function during exposure to light. Thus, this miRNA-mediated photoreceptor survival pathway is a novel target for potential therapy of retinal degenerative disorders. To evaluate the impact of the miR-183 cluster on photoreceptor survival more directly in the context of retinal degenerative disease, the consequences of miR-183 cluster loss-of-function will be evaluated in new mouse models of autosomal dominant and autosomal recessive retinitis pigmentosa. A knockout mouse model will be generated to determine the impact of complete loss of miRNA cluster activity. Additionally, a combination of 'top-down' and 'bottom-up' approaches will be employed to dissect out the molecular events underlying miRNA-mediated photoreceptor protection. Newly developed biochemical techniques will be used to identify functionally relevant direct targets of these miRNAs in the retina, and next generation sequencing technology will be employed to evaluate miRNA cluster-dependent alterations in gene expression that occur after exposure to intense light. Results of these investigations will provide insights into gene regulation networks involved in protecting photoreceptors against stress-induced death. These experiments promise to yield novel approaches to treat or prevent blinding diseases.